Cited by 1,237Renin-Angiotensin System StudiesSARS-CoV-2 and COVID-19 ResearchCOVID-19 Clinical Research Studies

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The pivotal link between ACE2 deficiency and SARS-CoV-2 infection

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Verdecchia, Paolo, Cavallini, Claudio, Spanevello, Antonio, Angeli, Fabio·2020·European Journal of Internal Medicine

DOI 10.1016/j.ejim.2020.04.037PMC PMC7167588

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Abstract

Angiotensin converting enzyme-2 (ACE2) receptors mediate the entry into the cell of three strains of coronavirus: SARS-CoV, NL63 and SARS-CoV-2. ACE2 receptors are ubiquitous and widely expressed in the heart, vessels, gut, lung (particularly in type 2 pneumocytes and macrophages), kidney, testis and brain. ACE2 is mostly bound to cell membranes and only scarcely present in the circulation in a soluble form. An important salutary function of membrane-bound and soluble ACE2 is the degradation of angiotensin II to angiotensin 1-7. Consequently, ACE2 receptors limit several detrimental effects resulting from binding of angiotensin II to AT1 receptors, which include vasoconstriction, enhanced inflammation and thrombosis. The increased generation of angiotensin 1-7 also triggers counter-regulatory protective effects through binding to G-protein coupled Mas receptors. Unfortunately, the entry of SARS-CoV2 into the cells through membrane fusion markedly down-regulates ACE2 receptors, with loss of the catalytic effect of these receptors at the external site of the membrane. Increased pulmonary inflammation and coagulation have been reported as unwanted effects of enhanced and unopposed angiotensin II effects via the ACE→Angiotensin II→AT1 receptor axis. Clinical reports of patients infected with SARS-CoV-2 show that several features associated with infection and severity of the disease (i.e., older age, hypertension, diabetes, cardiovascular disease) share a variable degree of ACE2 deficiency. We suggest that ACE2 down-regulation induced by viral invasion may be especially detrimental in people with baseline ACE2 deficiency associated with the above conditions. The additional ACE2 deficiency after viral invasion might amplify the dysregulation between the 'adverse' ACE→Angiotensin II→AT1 receptor axis and the 'protective' ACE2→Angiotensin 1-7→Mas receptor axis. In the lungs, such dysregulation would favor the progression of inflammatory and thrombotic processes triggered by local angiotensin II hyperactivity unopposed by angiotensin 1-7. In this setting, recombinant ACE2, angiotensin 1-7 and angiotensin II type 1 receptor blockers could be promising therapeutic approaches in patients with SARS-CoV-2 infection.

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RETRACTED ARTICLE: Angiotensin-converting enzyme 2/angiotensin-(1–7)/Mas axis prevents lipopolysaccharide–induced apoptosis of pulmonary microvascular endothelial cells by inhibiting JNK/NF–κB pathways
Li, Y., Cao, Y., Zeng, Z., Liang, M., Xue, Y., Xi, C., Zhou, M. S., & Jiang, W. (2015) · Scientific Reports · doi:10.1038/srep08209 · Cited by 104 · cited 1×
“[29, [31] [32] [33] ACE2 is expressed on the luminal side of the bronchial ciliated epithelia, where it removes a single amino acid residue also from the polypeptide des-Arg [9] bradykinin (DABK), [6] thereby preventing the binding of DABK on the bradykinin receptor B1 receptor.”
Background
Retracted
SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor
Hoffmann, M., Kleine-Weber, H., Schroeder, S., Krüger, N., Herrler, T., Erichsen, S., Schiergens, T. S., Herrler, G., Wu, N.-H., Nitsche, A., et al. (2020) · Cell · doi:10.1016/j.cell.2020.02.052 · Cited by 20,286 · cited 4×
“The present review discusses the role of angiotensin converting enzyme 2 (ACE2) receptors which are not only the door through which the virus enters into cells, [2,3] but also the conductor of several pathophysiological reactions associated with the clinical features of the disease, with potential therapeutic implicat…”
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“[69,70] In this context, administration of soluble recombinant ACE2 [12] or angiotensin1-7 [71] could be promising therapeutic approaches, requiring urgent evaluation in clinical trials.”
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“The present review discusses the role of angiotensin converting enzyme 2 (ACE2) receptors which are not only the door through which the virus enters into cells, [2,3] but also the conductor of several pathophysiological reactions associated with the clinical features of the disease, with potential therapeutic implicat…”
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Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus
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“[51] Pneumocytes type 2 are responsible for the production of alveolar surfactant, and in the same time they function as ‘stem’ cells, progenitors of pneumocytes type I (95% of all pneumocytes) which are responsible of gas exchanges.”
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“[54] Patients with hypertension were older that those without hypertension (66 vs 62 years, p=0.”
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“[56] Again, hypertension and history of cardiovascular disease were significantly more prevalent among the more severe patients.”
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“In humans, infection begins with the entry of SARS-CoV-2 into the cell through the spike protein, which interacts with the angiotensin-converting enzyme 2 (ACE2) receptor on the host cell membrane (Verdecchia et al., 2020).”
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“…enzyme 2 (Angiotensin I converting enzyme 2, ACE-2) may explain the observation of signs and symptoms of COVID-19 outside the respiratory tract (Verdecchia et al., 2020), particularly in the intestines, small blood vessels, muscles, and synovial tissue of joints (Li et al., 2020).”
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Background

Authors: Verdecchia, P., Cavallini, C., Spanevello, A., & Angeli, F.
Affiliations: University of Insubria (IT)
Corresponding author: Verdecchia, Paolo
ORCID: Verdecchia, Paolo
Cavallini, Claudio
Spanevello, Antonio
Angeli, Fabio
Venue: European Journal of Internal Medicine
Publisher: Elsevier BV
Published: 2020-06
Volume: 76
Pages: 14-20
ISSN: 0953-6205 (ISSN-L)
DOI: 10.1016/j.ejim.2020.04.037
PMC: PMC7167588
OpenAlex: W3017331996
Cited by: 1,237
References: 85
Citations by year: 2026: 22 · 2025: 50 · 2024: 84 · 2023: 156 · 2022: 245 · 2021: 384 · 2020: 295
FWCI: 45.93
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
Locations: European Journal of Internal Medicine (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
IrInSubria (University of Insubria) (submittedVersion)
Topics: Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Renin-Angiotensin System Studies
Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
Keywords: ACE2 receptor, COVID-19 pandemic, angiotensin II, angiotensin-(1-7), Mas receptor, angiotensin II type 1 receptor, lung inflammation, thrombosis, hypertension, diabetes mellitus, cardiovascular disease, angiotensin receptor blockers, COVID-19 severity
MeSH terms: Betacoronavirus, Angiotensin-Converting Enzyme 2, COVID-19, SARS-CoV-2, Angiotensins, Diabetes Mellitus, Heart Failure, Humans, Hypertension, Peptidyl-Dipeptidase A, Pneumonia, Viral, Receptors, Virus, Recombinant Proteins, Risk Factors, Coronavirus Infections, Angiotensin II Type 1 Receptor Blockers, Drug Discovery, Pandemics

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The pivotal link between ACE2 deficiency and SARS-CoV-2 infection

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